Atherosclerosis and other peripheral vascular diseases effect the quality of life of millions of people. Therefore, considerable attention has been directed towards understanding the etiology of hypercholesterolemia and hyperlipidemia and the development of effective therapeutic strategies.
Hypercholesterolemia has been defined as plasma cholesterol level that exceeds arbitrarily defined value called “normal” level. Recently, it has been accepted that “ideal” plasma levels of cholesterol are much below the “normal” level of cholesterol in the general population and the risk of coronary artery disease (CAD) increases as cholesterol level rises above the “optimum” (or “ideal”) value. There is clearly a definite cause and effect-relationship between hypercholesterolemia and CAD, particularly for individuals with multiple risk factors. Most of the cholesterol is present in the esterified forms with various lipoproteins such as low density lipoprotein (LDL), intermediate density lipoprotein (IDL), high density lipoprotein (HDL) and partially as very low density lipoprotein (VLDL). Studies clearly indicate that there is an inverse correlationship between CAD and atherosclerosis with serum HDL-cholesterol concentrations. (Stampfer et al., N. Engl. J. Med., 325 (1991), 373-381) and the risk of CAD increases with increasing levels of LDL and VLDL.
In CAD, generally “fatty streaks” in carotid, coronary and cerebral arteries, are found which are primarily free and esterified cholesterol. Miller et al., (Br. Med. J, 282 (1981), 1741-1744) have shown that increase in HDL-particles may decrease the number of sites of stenosis in coronary arteries of humans, and high level of HDL-cholesterol may protect against the progression of atherosclerosis. Picardo et al., (Arteriosclerosis 6 (1986) 434-441) have shown by in vitro experiments that HDL is capable of removing cholesterol from cells. They suggest that HDL may deplete tissues of excess free cholesterol and transfer them to the liver (Macikinnon et al., J. Biol. Chem. 261 (1986), 2548-2552). Therefore, agents that increase HDL cholesterol would have therapeutic significance for the treatment of hypercholesterolemia and coronary heart diseases (CHD).
Obesity is a disease highly prevalent in affluent societies and in the developing world and is a major cause of morbidity and mortality. It is a state of excess body fat accumulation. The causes of obesity are unclear. It is believed to be of genetic origin or promoted by an interaction between the genotype and environment. Irrespective of the cause, the result is fat deposition due to imbalance between the energy intake versus energy expenditure. Dieting, exercise and appetite suppression have been a part of obesity treatment. There is a need for efficient therapy to fight this disease since it may lead to coronary heart disease, diabetes, stroke, hyperlipidemia, gout, osteoarthritis, reduced fertility and many other psychological and social problems.
Diabetes and insulin resistance is yet another disease which severely effects the quality of life of a large population in the world. Insulin resistance is the diminished ability of insulin to exert its biological action across a broad range of concentrations. In insulin resistance, the body secretes abnormally high amounts of insulin to compensate for this defect; failing which, the plasma glucose concentration inevitably rises and develops into diabetes. Among the developed countries, diabetes mellitus is a common problem and is associated with a variety of abnormalities including obesity, hypertension, hyperlipidemia (J. Clin. Invest., (1985) 75:809-817; N. Engl. J. Med. (1987) 317:350-357; J. Clin. Endocrinol. Metab., (1988) 66: 580-583; J. Clin. Invest., (1975) 68:957-969) and other renal complications (See Patent Application No. WO 95/21608). It is now increasingly being recognized that insulin resistance and relative hyperinsulinemia have a contributory role in obesity, hypertension, atherosclerosis and type 2 diabetes mellitus. The association of insulin resistance with obesity, hypertension and angina has been described as a syndrome having insulin resistance as the central pathogenic link-Syndrome-X.
Hyperlipidemia is the primary cause of cardiovascular (CVD) and other peripheral vascular diseases. High risk of CVD is related to the higher LDL (Low Density Lipoprotein) and VLDL (Very Low Density Lipoprotein) seen in hyperlipidemia. Patients having glucose intolerance/insulin resistance in addition to hyperlipidemia have higher risk of CVD. Numerous studies in the past have shown that lowering of plasma triglycerides and total cholesterol, in particular LDL and VLDL and increasing HDL cholesterol help in preventing cardiovascular diseases.
Peroxisome proliferator activated receptors (PPAR) are members of the nuclear receptor super family. The gamma (γ) isoform of PPAR(PPARγ) has been implicated in regulating differentiation of adipocytes (Endocrinology, (1994) 135: 798-800) and energy homeostasis (Cell, (1995) 83: 803-812), whereas the alpha (α) isoform of PPAR (PPARα) mediates fatty acid oxidation (Trend. Endocrin. Metab., (1993) 4: 291-296) thereby resulting in reduction of circulating free fatty acid in plasma (Current Biol. (1995) 5: 618-621). PPARα agonists have been found useful for the treatment of obesity (WO 97/36579). It has been recently disclosed that the hypolipidaemic effect is enhanced when the molecule has both PPARα and PPARγ agonist activity and suggested to be useful for the treatment of syndrome X (WO 97/25042). Synergism between the insulin sensitizer (PPARγ agonist) and HMG CoA reductase inhibitor has been observed which may be useful for the treatment of atherosclerosis and xanthoma. (EP 0 753 298).
It is known that PPARγ plays an important role in adipocyte differentiation (Cell, (1996) 87, 377-389). Ligand activation of PPAR is sufficient to cause complete terminal differentiation (Cell, (1994) 79, 1147-1156) including cell cycle withdrawal. PPARγ is consistently expressed in certain cells and activation of this nuclear receptor with PPARγ agonists would stimulate the terminal differentiation of adipocyte precursors and cause morphological and molecular changes characteristics of a more differentiated, less malignant state (Molecular Cell, (1998), 465-470; Carcinogenesis, (1998), 1949-53; Proc. Natl. Acad. Sci., (1997) 94, 237-241) and inhibition of expression of prostate cancer tissue (Cancer Research (1998), 58:3344-3352). This would be useful in the treatment of certain types of cancer, which express PPARγ and could lead to a quite nontoxic chemotherapy.
Leptin resistance is a condition wherein the target cells are unable to respond to leptin signals. This may give rise to obesity due to excess food intake and reduced energy expenditure and cause impaired glucose tolerance, type 2 diabetes, cardio-vascular diseases and such other interrelated complications. Kallen et al (Proc. Natl. Acad. Sci., (1996) 93, 5793-5796) have reported that insulin sensitizers which perhaps due to their PPAR agonist expression and lower plasma leptin concentrations. However, it has been recently disclosed that compounds having insulin sensitizing property also possess leptin sensitization activity. They lower the circulating plasma leptin concentrations by improving the target cell response to leptin (WO 98/02159).
A few aryloxy alkanoic acids, their derivatives, and their analogs have been reported to be useful in the treatment of hyperglycemia and hypercholesterolemia. Some of such compounds described in the prior art are outlined below:
i) International publication No. WO 00/49005 disclose the compounds of general formula (II a)
wherein Het is an optionally substituted, saturated partially saturated or fully unsaturated 8 to 10 membered bicyclic ring, R1 is optionally substituted aryl or optionally substituted heteroaryl, R2 is hydrogen halogen, lower alkyl or lower alkoxy, L1 is an —R3-R4=linkage where R3 is alkylene, alkenylene or alkynylene and R4 is a direct bond, cycloalkylene, heterocycloalkylene, arylene, heteroarylidiyl, —C(=Z2)-NR5, NR5—C(=Z2), -Z2-, —C(═O), —C(═NOR5)—, —NR5—, N5—C(=Z2)-NR5, SO2—NR5 NR5—SO2, —O—C(═O)—, —C(═O)—O, —O—C(═O)—NR5, —NR5—C(═O)—O—; L2 is optionally substituted alkylene or alkenylene, Y is carboxy or an acid bioisostere and Z1 is NR5 and the corresponding N-oxides and their prodrugs and pharmaceutically acceptable salts and solvates.
An example of these compounds is shown in formula (II b)

ii) International publication No. WO 98/31359 disclose the compounds of general formula (IIc)X—Y-Z-Aryl-A-B  (IIc)wherein X represents NH2, NH—C(═NH)—, and the like or 5 or 6 membered monocyclic aromatic or nonaromatic ring system containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S wherein the mono or bicyclic ring system either substituted or unsubstituted, or a 9 to 14 membered polycyclic ring system, wherein one or more of the rings is aromatic and wherein the polycyclic ring system contains 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S, wherein the polycyclic ring system either substituted or unsubstituted; Y is selected from C0-8 alkylene, C0-8cycloalkyl, C0-8 alkylene-NR10—CO—C0-8 alkylene, C0-8alkylene-CONR10—C0-8 alkylene, C0-8 alkylene-O—C0-8 alkylene, C0-8 alkylene-NR10—C0-8 alkylene, C0-8 alkylene-S(O)0-2—C0-8 alkylene, C0-8 alkylene-S(O)0-2—NR10—C0-8 alkylene, C0-8 alkylene-NR10—S(O)0-2—C0-8 alkylene, C0-8 alkylene-CO—C0-8 alkylene, (CH2)0-6-aryl(CH2)0-6, (CH2)0-6-aryl-CO—(CH2)0-6, (CH2)0-6-aryl-CO—NR10-(CH2)0-6, (CH2)0-6-arylNR10CO(CH2)0-6, or (CH2)0-8—CH(OR1)(CH2)0-8; Z and A are each independently selected from (CH2)m, (CH2)mO(CH2)n, (CH2)mNR11(CH2)n, (CH2)mNR11CONR12(CH2)n, (CH2)mCONR11(CH2)n, (CH2)mCO(CH2)n, (CH2)mCS(CH2), (CH2)mNR11SO2(CH2)n, (CH2)mSNR11(CH2)n, (CH2)mSO2NR11(CH2)n, (CH2)mNR11SO12(CH2)n, (CH2)mCR11═CR2(CH2)n, (CH2)mC≡C(CH2)n; where m and n are each independently an integer from 0 to 6; Aryl is a 6 membered aromatic ring containing 0, 1, 2 or 3 nitrogen atoms and either unsubstituted or substituted with R8 and R9; B is
where p is an integer from 1 to 3, R6 is selected from hydrogen, fluorine, (C1-8) alkyl, hydroxy, hydroxy (C1-6) alkyl, carboxy (C0-6)alkyl, (C1-6) alkyloxy, (C1-6)alkylcarbonyl, aryl (C1-8) alkylcarbonyl, (C1-6)alkylcarbonyloxy, aryl (C0-6) alkylcarbonyloxy, (C1-6) alkylaminocarbonyloxy, (C3-8)cycloalkyl, aryl (C0-6) alkyl, (C0-6) alkylamino (C0-6) alkyl, (C0-6) dialkylamino (C0-6) alkyl, (C0-6) dialkylamino (C0-6) alkyl, (C1-8) alkylsulfonylamino (C0-6) alkyl, aryl (C0-6) alkylsulfonylamino (C06) alkyl, (C1-8) alkoxycarbonylamino (C0-8) alkyl, aryl (C0-8) alkyloxycarbonylamino (C0-8) alkyl, (C1-8) alkylcarbonylamino (C0-6) alkyl, aryl (C0-6) alkylcarbonylamino (C0-6) alkyl and the like; R7 is selected from (C7-20) polycyclyl (C1-8) alkylsulfonylamino (C0-8) alkyl and the like, R13 is selected from hydroxy, (C1-8) alkyloxy and the like;
An example of these compounds is shown in formula (IId)

iii) International publication No. WO 94/12181 disclose the compounds of general formula (IIe)X—Y-Z-Ary-A-B  (IIe)aryl is a 6 membered aromatic ring containing 0, 1, 2 or 3 nitrogen atoms and either unsubstituted or substituted with R8 and R9; X represents NH2, NH—C(═NH)—, and the like or 4 to 10 membered mono or polycyclic aromatic or nonaromatic ring system and containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S either unsubstituted or substituted; Y is selected from C0-8 alkyl, C4-10 cycloalkyl, C0-8 alkyl-NR3—CO—C0-8 alkyl, C0-8alkyl-CONR3—C0-8 alkyl, C0-8 alkyl-O—C0-8 alkyl, C0-8 alkyl-S(O)n—C0-8 alkyl, (CH2)0-8 aryl-(CH2)0-8, (CH2)0-6 aryl-SOn—, (CH2)0-8 aryl-CO—(CH2)0-8, (CH2)0-6 aryl-SO2—(CH2)0-6—, (CH2)0-6 NR3—(CH2)0-6—, (CH2)0-6 aryl-CH(OH)—(CH2)0-6—, (CH2)0-8—CONH—(CH2)0-8—, C0-8 alkyl-SO2—NR3—C0-8 alkyl, C0-8 alkyl-CO—C0-8 alkyl, C0-8 alkyl-CH(OH)-C0-8 alkyl, where n is an integer from 0-2; Z and A are independently chosen from (CH2)m, (CH2)mO(CH2)n, (CH2)mNR3(CH2)n, (CH2)mNR3(CH2)n, (CH2)mCONR11(CH2)n, (CH2)mCO(CH2)n, (CH2)mCS(CH2)n, (CH2)mSO2(CH2)n, (CH2)mS(CH2)n, (CH2)mSO2(CH2)n, (CH2)mSO(CH2)n, (CH2)mSO2NR3(CH2)n, (CH2)mNR3SO2(CH2)n, (CH2)mCR3═CR4(CH2)n, (CH2)mC≡C(CH2)n, (CH2)mCH(OH)(CH2)n; where m and n are each independently an integer from 0 to 6; Aryl is a 6 membered aromatic ring system containing 0, 1, 2, 3 or 4 N atoms and either unsubstituted or substituted with R5, provided that when A is (CH2)m, the Aryl ring, bonded by Z and A must contain at least one heteroatom;
B is
R6, R7, R8, R9, R10 and R11, are independently selected from hydrogen, fluorine, (C1-8) alkyl, hydroxy, hydroxy (C1-6) alkyl, carboxy (C0-6)alkyl, (C1-6) alkyloxy, aryl (C0-6) alkyloxy, (C3-8)cycloalkyl, aryl (C0-6) alkyl, (C1-6)alkylcarbonyloxy, (C0-6) alkylamino (C0-6) alkyl and the like;
R12 is selected from hydroxy, (C1-8) alkyloxy, aryl (C0-6) alkyl and the like;
An example of these compounds is shown in formula (IIf)

iv) International publication No. WO 93/16697 and U.S. Pat. No. 5,227,490 disclose the compounds of general formula (IIg)
wherein R1 is chosen independently from (C1-C6)alkyl, aryl(C4-C10)alkyl, aryl, carboxy, (C1-C6)alkyloxy, carboxy(C0-C6)alkyl, hydroxy(C0-C6)alkyl, (C1-C4)alkylsulfonyl(C0-C6)alkyl, (C0-C4)alkylamino(C0-C6)alkyl, aryl(C0-C10)alkylamino(C0-C6)alkyl, (C2-C10)acylamino(C0-C6)alkyl, (C1-C4)carboalkoxy(C0-C6)alkyl or halogen atom; R2 is chosen from hydrogen, halogen, hydroxy, (C1-C6)alkyloxy, aryl(C0-C4)alkyl, aryl(C0-C6)alkyloxy, (C1-C6)alkyl wherein the alkyl group is unsubstituted or substituted with one or more groups chosen from hydroxy, (C1-C4)alkyloxy, amino(C1-C10) alkylcarbonyl, aryl(C0-C10)alkylcarbonyl, aryl(C0-C10)alkylcabonylamino, (C1-C6) alkylsulfonyl, aryl(C0-C6)alkylsulfonyl, (C1-C6)alkylsulfonylamino, aryl(C0-C10) alkylsulfonylamino, (C1-C10)alkyloxycarbonylamino, aryl(C0-C6)alkylamino, aryl(C0-C6)alkylcarbonylamino, amino, carboxy, aryl, carbonyl-P-or SO2—P wherein P is a single L or D amino acid or a sequence of 2-4 L or D amino acids connected by amide linkage; or R2 represents carboxyl, (C1-C6)alkylcarbonyl, aryl(C1-C10)alkylcarbonyl, (C1-C6)alkyloxycarbonylamino(C1-C6)alkyl, (C1-C6)alkylaminocarbonylamino(C1-C6)alkyl, aryl(C0-C6)alkylaminocarbonylamino(C1-C6)alkyl, aryl(C0-C6)alkyloxycarbonylamino (C1-C6)alkyl, (C1-C6)alkoxycarbonyl or aryl(C0-C6)alkyloxycarbonyl and provided that when there is more than one R2 on the same carbon atom they may be the same or different; R3 is hydrogen, (C1-C6)alkyl, aryl(C1-C10)alkyl; Z is NR4R5 wherein R4 and R5 are independently hydrogen, (C1-C6)alkyl, aryl(C1-C10)alkyl wherein said alkyl groups are unsubstituted or substituted with (C1-C4)alkyloxy, carboxy (C0-C6)alkyl, hydroxy, halogen or Z represents a 4-9 membered mono or bicyclic ring system containing 1, 2 or 3 heteroatoms chosen from N, O or S and either unsubstituted or substituted with R4 or R5 or

Y is (C1-C10)alkyl either unsubstituted or unsubstituted with one or more groups selected from R4 or R5; or Y represents (C4-C8)cycloalkyl, aryl, (C0-C3)alkylaryl(C0-C3)alkyl, (C0-C3)alkylaryl(C0-C3)alkylcarbonyl, (C0-C3)alkylaryl (C0-C3)alkylcarboxamido, (C0-C3)alkylaryloxy(C0-C3)alkyl, (C0-C3)alkyloxy(C0-C6)alkyl,
or —(CH2)m—Q—(CH)n where Q is a C2-C8 membered heterocyclic ring containing 1, 2 or 3 heteroatoms chosen from N, O or S and substituted or unsubstituted with oxo, thio, or (C1-C6)alkyl and m and n are chosen from the integers 0, 1, 2 or 3; X is O, S, SO, SO2, CO, —NR4CO—, CONR4—, —CH2—, —CH═CH—, —C═C—, —NR4CS—, —CSNR4— or SO2NR4 or NR4SO2;An example of these compounds is shown in formula (IIh)

v) International publication No. WO 00/05223 disclose the compounds of general formula (IIi)
where A is a bicyclic heteroaryl, optionally substituted with one or more substituents; B is linker group connecting group A to groups D and comprising a 3 or 4 atom linker where each atom is independently selected from carbon, oxygen, nitrogen and sulphur and is optionally substituted with one or more C1-6 alkyl groups or two of such adjacent alkyl substituents may form a ring; C is aryl or mono or bicyclic heteroaryl, each or which can be optionally substituted; D is an aryl or heteroaryl, both or which are optionally substituted, R1 is hydrogen, C1-5 alkyl, C1-3 alkanoyl, or C1-3 alkoxycarbonyl, R2 to R5 are each independently selected from hydrogen, C1-6 alkyl, aryl and heteroaryl containing up to 2 heteroatoms chosen from oxygen, sulphur and nitrogen, the aryl and heteroaryl optionally substituted with C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 alkoxy, C1-4 alkanoyl, C1-6 alkylamino, C1-4 alkylC1-6 alkyloxy, C1-6alkylaminoC1-6alkyl, nitro, cyano, halogen, trifluoromethyl, hydroxy, (CH2)pOH where p is 1 or 2, —CORa and —CONRaRb, where Ra and Rb are independently selected from hydrogen and C1-6 alkyl or two of R2 to R5 can be taken together to form a 3 to 7 membered ring, R6 is an acidic functional group, r and s are each independently 0 or with the proviso that r and s cannot both be 0.
An example of these compounds is shown in formula (IIj)

vi) International publication No. WO 00/64888 disclose the compounds of general formula (IIk)

Ar1 and Ar2 are independently aryl, fused arylcycloalkenyl, fused arylcycloalkyl, fused arylheterocyclenyl, fused arylheterocyclyl, heteroaryl, fused heteroarylcycloalkenyl, fused heteroarylcycloalkyl, fused heteroarylcyclenyl or fused heteroarylheterocyclyl; A is O, S, SO, OS2, NR13C(O), NR14C(O), C(O)NR14, NR14C(O)N(R15), C(R14)═N; chemical bond and the like; B is O, S, NR19, a chemical bond, C(O), N(R20)C(O) or C(O)N(R20); E is a chemical bond or an ethylene groups; a is 0-6; b is 0-4; c is 0-4; d is 0-6; g is 1-5; h is 1-4; R1, R3, R5 and R7 are independently hydrogen, halogen alkyl, carbonyl, alkoxycarbonyl, or aralkyl; R2, R4, R6 and R8 are independently —(CH2)q—X; q is 0-3; X is hydrogen, halogen, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, alkoxy, aralkoxy, heteroaralkoxy, carbonyl, alkoxycarbonyl, tetrazolyl, acyl, acylHNSO2, and the like; Z is R21O2C, R21OC, cyclo-imide; CN, R21O2SHNCO, R21O2SNH, R21NCO, R21O-2,4-thiazolidinonyl or tetrazolyl.
An example of these compounds is shown in formula (III)
